Hydantoins and method fob obtaining



Patented Apr. 5, 1949 UNITED STATES PATENT OFFICE Loren M. Long, Detroit, Mich, 'assignor to Parke,

Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application March '11, 1946, Serial No. 653,711

Claims. 1 This invention relates to 1-allyl-5-phenylhydantoin and its alkali metal salts and also to a method for obtaining these products 1-allyl-5- phenylhydantoin has the formula,

QIH-n-ommhom The new compounds of'the present invention are powerful anticonvulsants and are particularly valuable in the treatment of the grand mal form of epilepsy.

The use of hydantoins in the treatment of epilepsy is well-known to the art. The most effective compounds of this type are probably those which contain two hydrocarbon substituents in the five position. Some other 5,'5-disubst'ituted hydantoins which have proved of value are those which have an additional substituent(s) in the one and/ or three positions of the ring. However, in general, the hydantoins which have only one hydrocarbon substituent in the five position show very little or no anticonvulsive activity. I have found this to be particularly true of the l-alkyl- S-phenyl hydantoins. These particular hydantoin derivatives possess no activity as anticanvulsants and are, in addition, very toxic compounds. It was surprising to find that 1-allyl-5- phenyl hydantoin is an extremely potent and nontoxic anticonvulsant since the only structural difierence between this compound and the inactive and toxic 1-alkyl-5-phenyl hydantoins is that the compounds of the present invention have an unsaturated alkyl rather than a saturated alkyl radical in the one position of the ring. Perhaps even more surprising was the discovery that replacing the hydrogen atom in the five position of the hydantoin ring in 1-allyl-5-phenyl hydantoin by an alkyl radical results in the formation of a class of hydantoin compounds which are almost completely devoid of anticonvulsant activity and which are extremely toxic.

Some of the 5,5-disubstituted hydantoins of the prior art, for example 5,5-diphenyl hydantoin, suffer the disadvantage that they must be administered in the form of their alkali metal salts in order to obtain the maximal therapeutic eifect. However, in accordance with my invention I have found that it is not necessary to administer 1-allyl-5-phenyl hydantoin as its alkali metal salts since the free hydantoin produces just as beneficial a therapeutic effect as its alkali metal salts. The compounds of the present invention may be conveniently administered by the oral route to human patients suffering from-epilepsy. In the case of children over the age of six the average daily dose is between about 0.2 and 0.4 gram per day while the dosage for adults is usually about -.0.6 gram per day. For best results and prolonged therapeutic effect about 0.2 gram of the drug should be taken before each meal.

I have found that ,1-allyl-5-phenylhydantoin maybe prepared by a unit process starting with benzaldehyde cyanohydrin and allyl amine. The first step in this unit process is to react the benzaldehyde cyanohydrin and the allyl amine to obtain the corresponding aminonitrile, This phase or .step of the process is usually carried out by simply bringing the two reactants together in an inert organic solvent such as ether'or benzene. After the formation of the aminonitrile is complete, the water layer which separates from the mixture is withdrawn and the solvent distilled. The next step in the process is the treatment of the crude aminonitrile with potassium cyanate in the presence of acid at about 5 C. .to obtain the corresponding ureido nitrile which is then hydrolyzed by boiling with acid to obtain the desired hydantoin. In the prior art the reaction between similar aminonitriles and potassium cyanate has always been carried out in the presence of weak acids such as acetic acid while the subsequent hydrolytic reaction has been effected by boiling the ureido nitrile with mineral acid. However, in this particular case I have found that the reaction between the aminonitrile and the cyanate salt may also be carried out below about 10 C. in the presence of a strong mineral acid such as hydrochloric or hydrobromic acid and the resultant ureido nitrile subsequently hydrolyzed by merely boiling the solution. In general, it is not necessary to add any more mineral acid before hydrolyzing the ureido nitrile although if rather dilute mineral acid is used in the cyanate-aminonitrile reaction, it is sometimes advisable to add a small amount of mineral acid to insure completeness of the hydrolysis reaction. The chief advantages of my modified process over the analogous processes of the prior art lie principally in its simplicity and lower cost.

The alkali metal salts of 1-allyl-5-phenylhydantoin may be conveniently prepared by dissolving the hydantoin in excess sodium or potassium hydroxide and precipitating the salt from the solution by addition of a Water-miscible organic solvent such as methanol, ethanol, n-propanol, acetone, dioxane and the like, Alternatively, equivalent amounts of sodium or potassium hydroxide and the hydantoin may be reacted in aqueous solution and the resulting aqueous solution of the salt evaporated to dryness under reduced pressure. The alkali metal salts of 1-ally1-5-phenyl hydantoin obtained by either of these two procedures are white, water-soluble, amphorous powders which are, because of their water-solubility, particularly useful for oral administration of this valuable therapeutic agent.

The invention is illustrated by the following specific example without limitingit thereto.

39.9 g. of benzaldehyde cyanohydrin dissolved in 50- cc. of ether is mixed with 17.1 g. of allyl amine. The solution turns yellow and becomes quite warm and as the reaction proceeds the water which is formed separates. After the reaction is complete, the water is drawn off and the ether evaporated. The thick liquid residue which consists of the intermediate aminonitrile is added to a solution of 42 cc. of concentrated hydrochloric acid and 300 cc. of water. The resulting solution is cooled to 5 C. and a total of 30 got potassium cyanate added in small portions with frequent shaking. After all the cyanate is added, the mixture is allowed to stand in an ice bath for one-half hour and then heated on a steam bath for one-half hour. 300 cc. of concentrated hydrochloric acid is added and the mixture evaporated to dryness. The residue which consists of the crude 1-allyl-5-phenylhydantoin is washed with 300 cc. of cold water and then dissolved in dilute sodium hydroxide solution. The alkaline solution is decolorized by treatment with activated charcoal, filtered and the product reprecipitated by acidifying the filtrate with hydrochloric acid. The crude hydantoin is finally purified by recrystallization from alcohol-water mixture to yield 32 g. of th pure white crystalline product; M. P. 955 C.

g. of 1-allyl-5-phenyl hydantoin is dissolved in a small amount of water containing 1.85 of sodium hydroxide and the resulting solution evaporated to dryness under reduced pressure. The light colored, amphorous residue consists of the desired sodium salt of 1-allyl-5-phenyl hydantoin.

' By substituting an equivalent amount of potassium hydroxide for sodium hydroxide in this pro-' cedure, one obtains the potassium salt. Instead of evaporating the solution, the salt can be pre- Number cipitated from the reaction mixture by the addition of n-propanol.

Another method of preparing the salts of the present invention consists in adding an alcoholic solution of the hydantoin to an alcoholic solution of sodium or potassium hydroxides or ethylates. For example, 10 g. of thehydantoin dissolved in absolute ethanol is added to an absolute ethanol solution containing 4 g. of potassium ethylate. The white potassium salt which separates is removed by filtration, washed with alcohol and dried.

What I claim as my invention is:

1. A compound of the class consisting of l-allyl- 5-phenyl hydantoin and its corresponding alkali metal salts.

2. 1-Allyl-5-phenyl hydantoin.

3. The sodium salt of l-allyl-5-phenyl hydantoin.

4. The potassium salt of 1-ally1-5-phenyl hydantoin. 1

5. A unit process for the preparation of l-allyl- 5-phenyl hydantoin which comprises reacting benzaldehyde cyanohydrin with allyl amine in an inert organic solvent, removing said solvent from the reaction mixture, reacting the crude aminonitrile so formed with an alkali metal cyanate at a temperature below about 10 C. and in the presence of aqueous mineral acid, hydrolyzing the intermediate ureido nitrile by heating the acidic reaction mixture and isolating the product so formed.

LOREN M. LONG.

REFERENCES CITED FOREIGN PATENTS Country Date France June 11, 19 34 OTHER REFERENCES Jour. fur Praktische Chemie (2) vol. 66 (1902), page 236.

Karrer, Organic Chemistry, (1946), page 283.

2nd edition 

